Projects:

1) Podocyte biology and protective signaling. We have identified several molecular pathways that strongly protect podocytes from injury. The goal is to develop novel pharmacological strategies to enhance these signals in patients with proteinuric kidney disease.

a) Podocyte Rap1 signaling. We have shown that activation of podocyte Rap1, a small GTPase critical to multiple fundamental biological processes, is diminished in many forms of proteinuric kidney disease and that enhancing Rap1 activation in the setting of podocyte injury is strongly protective. Our work demonstrates that the activation state of podocyte Rap1 is controlled by many upstream factors, both positive and negative, that converge to maintain its proper homeostasis. Two upstream genes in particular, Rap1gap and Magi2, are critical regulators of Rap1 activation in glomerular disease. Our lab is working to establish their physiological and pathophysiological functions in various disease processes, to validate their importance in human glomerular disease, and to pinpoint ways to manipulate them pharmacologically to improve podocyte function in glomerular disease.

b) Dach1 transcriptomic signal in podocytes. We found Dach1 to be essential to podocyte function in both novel global and podocyte-specific knock out mouse models. Interestingly, podocyte-specific Dach1 heterozygous mice, which have reduced glomerular Dach1 expression levels similar to human diabetic kidney disease (DKD) patients, showed increased susceptibility to DKD. Current studies are focused on understanding transcriptomic regulation of podocyte genes by Dach1. We are also interested in novel small molecules that stimulate Dach1 expression.

2) Cross-talk by extracellular vesicles in kidney disease pathogenesis. Our lab utilizes genetic models to track and study the fate of parent cell-specific extracellular vesicles (EVs) both locally within the glomerulus and in the setting of long distance interorgan communication.

a) Podocyte-to-parietal epithelial cell communication by EVs in proliferative glomerulopathy. In proliferative glomerulonephritis such as rapidly progressive GN, podocyte injury causes pathogenic activation and unchecked proliferation of neighboring parietal epithelial cells (PECs) resulting in an agglomeration of activated PECs in Bowman’s space and crescent formation. We have identified strong uptake of podocyte-derived EVs by PECs in proliferative GN and that these EVs drive PEC proliferation and activation. We are identifying involved mechanisms including responsible podocyte-derived EV cargo microRNAs.

b) Role of heart-to-kidney signal by cardiac-derived EVs in cardiorenal syndrome type 1. We are interested in understanding the interaction of heart and kidney by EVs in Cardiovascular-Kidney-Metabolic (CKM) Syndrome, where problems in one area worsens the others. We identify a new mechanism of CRS type 1 that involves direct maladaptive heart-to-kidney communication by cardiac-origin EVs depositing in and injuring kidney cells. Our lab is investigating involved mechanisms including identification of involved cardiac-derived EV cargo molecules and impacts on recipient kidney cells.